This invention concerts certain novel quinazoline derivatives which possess pharmacological properties of use in the treatment of autoimmune diseases or medical conditions, for example T cell mediated disease such as transplant rejection or rheumatoid arthritis. The invention also concerns processes for the manufacture of the quinazoline derivatives of the invention, pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of inhibition of T cell mediated disease.
A critical requirement of the immune system is the ability to differentiate between xe2x80x9cselfxe2x80x9d and xe2x80x9cnon-selfxe2x80x9d (i.e. foreign) antigens. This discrimination is required to enable the immune system to mount a response to foreign proteins such as those on the surface of pathogens whilst maintaining tolerance to endogenous proteins and thereby preventing damage to normal tissues. An autoimmune disease results when self-tolerance breaks down and the immune system reacts against tissues such as the joints in rheumatoid arthritis or nerve fibres in multiple sclerosis. Stimulation of the human immune response is dependent on the recognition of protein antigens by T cells. However T cells do not become activated by and respond to antigen alone but are only triggered into action when the antigen is complexed with major histocompatibility complex (MHC) molecules on the surface of an antigen-presenting cell such as a B cell, macrophage or dendritic cell. Thus T cell activation requires the docking into the T cell receptor of the peptide/MHC complex expressed on an antigen-presenting cell. This interaction, which confers the antigen specificity to the T cell response, is essential for full activation of T lymphocytes. Subsequent to this docking, some of the earliest signal transduction events leading to full T cell activation are mediated through the action of multiple tyrosine-specific protein kinases (E. Hsi et al., J. Biol. Chem., 1989, 264, 10836) including p56lck and ZAP-70. The tyrosine kinase p56lck is a lymphocyte specific member of the src family of non-receptor protein tyrosine kinases (J. D. Marth et al., Cell, 1985, 43, 393). The enzyme is associated with the inner surface of the plasma membrane where it binds to the T cell receptor associated glycoproteins CD4 (in helper T cells) and CD8 (in cytotoxic or killer T cells) (C. E. Rudd et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 5190 and M. A. Campbell et al., EMBO J, 1990, 9, 2125).
It is believed that p56lck tyrosine kinase plays an essential role in T cell activation as, for example, the loss of p56lck expression in a human Jurkat T cell line prevents the normal T cell response to stimulation of the T cell receptor (D. B. Straus et al., Cell, 1992, 70, 585) and a deficiency in p56lck expression causes severe immune deficiency in humans (F. D. Goldman et al., J. Clin. Invest., 1998, 102, 421).
Certain autoimmune conditions or diseases such as inflammatory diseases (for example rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis and lung fibrosis), multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, allergic asthma and insulin-dependent diabetes are believed to be associated with inappropriate T cell activation (see, for example, J. H. Hanke et al., Inflamm. Res., 1995, 44, 357). In addition the acute rejection of transplanted organs can also be interpreted as a consequence of inappropriate T cell activation. Therefore, compounds which modulate T cell activation by way of inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to full T cell activation, for example by way of inhibition of p56lck tyrosine kinase, are expected to provide therapeutic agents for such pathological conditions.
Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds modulate T cell activation by way of inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to full T cell activation, for example by way of inhibition of p56lck tyrosine kinase.
In particular, the quinazoline derivatives of the invention are expected to be useful as immunoregulation or immunosuppressive agents for the prevention or treatment of organ rejection following transplant surgery.
Agents of this kind would offer therapy for transplant rejection and autoimmune diseases whilst avoiding toxicities associated with the commonly used, less selective immunosuppressants. The leading agent for the prevention or treatment of transplant rejection is cyclosporin A which, although effective, is often associated with side-effects such as renal damage and hypertension which results in kidney failure in a substantial number of patients. It is contemporary practice to treat rheumatoid arthritis initially with symptom relief agents such as NSAIDs, which do not have any beneficial effect on disease progression and are often associated with unwanted side-effects. A rationally based, disease modifying agent, without such deleterious side-effects, would therefore offer significant benefits in the prevention or treatment of transplant rejection or autoimmune conditions such as rheumatoid arthritis.
As stated above, the present invention is based, in particular, on the discovery that the quinazoline derivatives of the invention modulate T cell activation by way of inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to full T cell activation. Accordingly compounds of the present invention possess higher inhibitory potency against particular non-receptor tyrosine kinases such as p56lck tyrosine kinase than against other non-receptor tyrosine kinases or against receptor tyrosine kinases (RTKs) such as epidermal growth factor (EGF) RTX. In general, the quinazoline derivatives of the invention possess sufficient potency in inhibiting non-receptor tyrosine kinases such as p56lck tyrosine kinase that they may be used in an amount sufficient to inhibit, for example, p56lck tyrosine kinase whilst demonstrating reduced potency, preferably whilst demonstrating no significant activity, against RTKs such as EGF RTK. Thus the quinazoline derivatives of the invention can be used in the clinical management of those particular diseases which are sensitive to inhibition of such non-receptor tyrosine kinases, for example autoimmune diseases or medical conditions, for example T cell mediated disease such as transplant rejection or rheumatoid arthritis.
It is disclosed by K. H. Gibson et al., Bioorganic and Medicinal Chemistry Letters, 1997, 7, 2723-2728 that certain-4-anilinoquioline derivatives possess useful EGF RTK inhibitory properties. It is also disclosed that 1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea is inactive as an EGF RTK inhibitor.
It is disclosed in International Patent Application WO 98/50370 that certain 5-substituted quinazoline derivatives may be useful as inhibitors of serine/threonine protein kinases. Whilst most of the examples are 4-amino-5-phenoxyquinazolines, there is the disclosure of three 4-ureido-5-phenoxyquinazolines, namely of:
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea and
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea.
It is disclosed by C. I. Hong et al, J. Med. Chem., 1976, 19, 555-558 that certain 4-aminopyrazolo[3,4-d]pyrimidine derivatives possess growth inhibitory activity against cultured L1210 leukaemia cells. The disclosed compounds include:
1-phenyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(3-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(4-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-fluorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-benzyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea and
1-(3-phenylpropyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea.
It is disclosed in International Patent Application WO 97/03069 that certain quinoline and quinazoline derivatives may be useful as protein tyrosine kinase inhibitors. All of the disclosed examples are 4-heteroarylaminoquinazoline derivatives and none of them are 1-heteroaryl-3-(quinazolin-4-yl)urea derivatives.
It is disclosed in International Patent Application WO 98/43960 that certain 3-cyanoquinoline derivatives may be useful as protein tyrosine kinase inhibitors. Almost all of the 398 disclosed examples were 3-cyano-4-anilinoquinoline or 3-cyano-4-benzylaminoquinoline derivatives. There is no disclosure of any (3-cyanoquinolin-4-yl)urea derivatives.
It is disclosed in International Patent Application WO 99/69024 that certain 1-phenyl-3-(quinolin-4-yl)urea derivatives may be useful as antagonists of the human HFGAN72 receptor, a G-protein coupled neuropeptide receptor, and hence may be of potential use in the treatment of obesity. There is no disclosure as examples of any 1-phenyl-3-(quinazolin-4-yl)urea or 1-phenyl-3-(3-cyanoquinolin-4-yl)urea compounds.
According to one aspect of the invention there is provided a quinazoline derivative of the Formula I 
wherein Q1 is a quinazoline-like ring such as a group of the formula Ia, Ib, Ic or Id 
wherein:
Y1 together with the carbon atoms to which it is attached forms a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S provided that the group of formula Ic so formed is not a purine ring;
Y2 together with the carbon atoms to which it is attached forms a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S;
m is 0, 1, 2, 3 or 4;
each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)akenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
Q3xe2x80x94X1xe2x80x94
xe2x80x83wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (1-6C)alkyl, and Q3 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R1)m is (1-3C)alkylenodioxy,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CHxe2x95x90CH and Cxe2x89xa1C wherein R5 is hydrogen or (1-6C)alkyl,
and wherein any CH2xe2x95x90CHxe2x80x94 or HCxe2x89xa1Cxe2x80x94 group within a R1 substituent optionally bears at the terminal CH2xe2x95x90 or HCxe2x89xa1 position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is a direct bond or is selected from CO and N(R6)CO, wherein R6 is hydrogen or (1-6C)alkyl, and Q4 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
xe2x80x94X3xe2x80x94Q5
xe2x80x83wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R7), CO, CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (1-6C)alkyl, and Q5 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(4C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl)sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
xe2x80x94X4xe2x80x94R8
xe2x80x83wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (1-6C)alkyl, and R8 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1-6C)alkoxycarbonylamino-(1-6C)alkyl, or from a group of the formula:
xe2x80x94X5xe2x80x94Q6
xe2x80x83wherein X5 is a direct bond or is selected from O and N(R10), wherein R10 is hydrogen or (1-6C)alkyl, and Q6 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and any Q6 group optionally bears 1 or 2 substituents, which may be the same or different, selected from halogeno, (1-6C)alkyl and (1-6C)alkoxy,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents;
R2 is hydrogen or (1-6C)alkyl and R1 is hydrogen or (1-6C)alkyl, or R2 and R3 together form a CH2, (CH2)2 or (CH2)3 group;
Z is O, S, N(Cxe2x89xa1N) or N(R11), wherein R11 is hydrogen or (1-6C)alkyl; and
Q2 is aryl, aryl-(1-3C)alkyl, aryl-(3-7C)cycloalkyl, heteroaryl, heteroaryl-(1-3C)alkyl or heteroaryl-(3-7C)cycloalkyl wherein each aryl group is phenyl or naphthyl and each heteroaryl group is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Q2 is optionally substituted with 1, 2, 3 or 4 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
xe2x80x94X6xe2x80x94R12
xe2x80x83wherein X6 is a direct bond or is selected from O and N(R13), wherein R13 is hydrogen or (1-6C)alkyl, and R12 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:
xe2x80x94X7xe2x80x94Q7
xe2x80x83wherein X7 is a direct bond or is selected from O, S, SO, SO2, N(R14), CO, CH(OR14), CON(14), N(R14)CO, SO2N(R14), N(R14)SO2, C(R14)2O, C(R14)2S and C(R14)2N(R14), wherein each R14 is hydrogen or (1-6C)alkyl, and Q7 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or Q2 is optionally substituted with a (1-3C)alkylenedioxy group,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on Q2 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
xe2x80x94X8xe2x80x94R15
xe2x80x83wherein X8 is a direct bond or is selected from O and N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and R15 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl-(1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on Q2 optionally bears 1 or 2 oxo or thioxo substituents;
or a pharmaceutically-acceptable salt thereof;
provided that the compounds:
1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea,
1-[-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea,
1-phenyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(3-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(4-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-fluorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-benzyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea and
1-(3-phenylpropyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea are excluded.
In this specification the genetic term xe2x80x9calkylxe2x80x9d includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as xe2x80x9cisopropylxe2x80x9d are specific for the branched-chain version only. An analogous convention applies to other generic terms.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
It is to be understood that the hydrogen atom which is shown at the 2-position in each of the part structures of the formulae Ia, Ib, Ic and Id indicates that position remains unsubstituted by any R1 group.
Suitable values for the generic radicals referred to above include those set out below.
A suitable value for any one of the xe2x80x98Qxe2x80x99 groups (Q2 to Q7) when it is aryl or for the aryl group within a xe2x80x98Qxe2x80x99 group is, for example, phenyl or naphthyl, preferably phenyl.
A suitable value for a (3-7C)cycloalkyl group within Q2 or for Q3 or Q4 when it is (3-7C)cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl and a suitable value for Q3 or Q4 when it is (3-7C)cycloalkenyl is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
A suitable value for Q2 when it is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, indolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl, preferably isoxazolyl, 1,2,3-triazolyl, pyridyl, benzothiazolyl, quinolyl or quinazolinyl.
A suitable value for any one of the xe2x80x98Qxe2x80x99 groups, Q3 to Q7,when it is heteroaryl or for the heteroaryl group within a xe2x80x98Qxe2x80x99 group is, for example, an aromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl, preferably thienyl, 1,2,3-triazolyl, pyridyl, quinolyl, quinazolinyl or quinoxalinyl.
A suitable value for any one of the xe2x80x98Qxe2x80x99 groups, Q3 to Q7, when it is heterocyclyl or for the heterocyclyl group within a xe2x80x98Qxe2x80x99 group is, for example, a non-aromatic saturated or partially saturated 3 to 10-membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulphur, for example oxiranyl, oxetanyl, tetrahydrofyranyl, tetrahydropyranyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, hydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, homopiperidin-1-yl, piperazin-1-yl or homopiperazin-1-yl, more preferably piperidinyl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
A suitable value for a xe2x80x98Qxe2x80x99 group when it is heteroaryl-(1-6C)alkyl is, for example, heteroarylmethyl, 2-heteroarylethyl and 3-heteroarylpropyl. The invention comprises corresponding suitable values for xe2x80x98Qxe2x80x99 groups when, for example, rather than a heteroaryl-(1-6C)alkyl group, an aryl-(1-6C)alkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl-(1-6C)alkyl or heterocyclyl-(1-6C)alkyl group is present.
When, as defined hereinbefore, Y1 together with the carbon atoms to which it is attached forms a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S (provided that the group of formula Ic so formed is not a purine ring), ring Y1 is suitably unsaturated or partially unsaturated wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94COxe2x80x94 group and a ring nitrogen atom may optionally bear a (1-6C)alkyl group. Diradicals of suitable fused Y1 rings include thiendiyl, furandiyl, pyrazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl, isothiazolediyl, 1,2,3-oxadiazolediyl, 1,2,3-triazolediyl, pyridinediyl pyrimidinediyl, pyrazinediyl, pyridazinediyl and 1,3,4-triazinediyl. Examples of suitable bicyclic rings of formula Ic formed by the fusion of ring Y1 to the adjacent pyrimidine ring include fluropyrimidinyl, thienopyrimidinyl, pyrrolopyimidinyl, pyrrolinopyrimidinyl, oxopyrrolinopyrimidinyl, oxazolopyrimidinyl, oxazolinopyrimidinyl, oxooxazolinopyrimidinyl, isoxazolopyrimidinyl, thiazolopyrimidinyl, thiazolinopyrimidinyl, oxothazolinopyrimidinyl, isothiazolopyrimidinyl, oxoimidazolinopyrimidinyl, pyrazolopyrimidinyl, pyrazolinopyrimidinyl, oxopyrazolinopyrimidinyl, pyridopyrimidinyl, pyrimidopyrimidinyl and pteridinyl. Preferably the bicyclic ring of formula Ic is furo[3,2-d]pyrimidinyl, furo[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, oxazolo[5,4-d]pyrimidinyl, oxazolo[4,5-d]pyrimidinyl, thiazolo[5,4-d]pyrimidinyl, thiazolo[4,5-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,5-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrimido[4,5-d]pyrimidinyl, pyrimido[5,6-d]pyrimidinyl or pteridinyl. More specifically the bicyclic ring of formula Ic is 6-oxopyrrolino[2,3-d]pyrimidin-4-yl, 6-oxopyrrolino[3,2-d]pyrimidin-4-yl, 2-oxooxazolino[5,4-d]pyrimidin-7-yl, 2-oxothiazolino[5,4-d]pyrimidin-7-yl, 2-oxooxazolino[4,5-d]pyrimidin-7-yl, 2-oxothiazolino[4,5-d]pyrimidin-7-yl, 2-oxoimidazolino[4,5-d]pyrimidin-7-yl, 3-oxopyrazolino[3,4-d]pyrimidinyl or 3-oxopyrazolino[4,3-d]pyrimidin-7-yl. Further preferred bicyclic rings of formula Ic include thieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thiazolo[5,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl and pteridinyl, more specifically thieno[3,2-d]pyrimidin-4-yl, thieno[2,3-d]pyrimidin-4-yl, thiazolo[5,4-d]pyrimidin-7-yl, pyrido[2,3-d]pyrimidin-4-yl, pyrido[3,4-d]pyrimidin-4-yl, pyrido[4,3-d]pyrimidin-4-yl, pyrido[3,2-d]pyrimidin-4-yl and pteridine-4-yl.
When, as defined hereinbefore, Y2 together with the carbon atoms to which it is attached forms a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S, ring Y2 is suitably unsaturated or partially unsaturated wherein a xe2x80x94CH2xe2x80x94 group can optionally be replaced by a xe2x80x94COxe2x80x94 group and a ring nitrogen atom may optionally bear a (1-6C)alkyl group. Diradicals of suitable fused Y2 rings include thiendiyl, furandiyl, imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl, isothiazolediyl, 1,2,3-oxadiazolediyl, 1,2,3-triazolediyl, pyridinediyl, pyrimidinediyl, pyraziediyl, pyridazinediyl and 1,3,4-triazinediyl. Examples of suitable tricyclic rings of formula Id formed by the fusion of ring Y2 to the adjacent quinazoline ring include imidazoquinazolinyl, oxazoloquinazolinyl, thiazoloquinazolinyl, [1,2,3]triazoloquinazolinyl, pyrazoloquinazolinyl, pyrroloquinazolinyl oxoimidazolinoquinazolinyl, oxooxazolinoquinazolinyl, oxothiazolinoquinazolinyl and oxopyrazolinoquinazolinyl. Preferably the tricyclic ring of formula Id is 3H-imidazo[4,5-g]quinazolinyl, oxazolo[4,5-g]quinazolinyl, thiazolo[4,5-g]quinazolinyl, 3H-[1,2,3]triazolo[4,5-g]quinazolinyl, 1H-pyrazolo[3,4-g]quinazolinyl, 6H-pyrrolo[2,3-g]quinazolinyl, 2-oxo-1,2-dihydro-3H-imidazo[4,5-g]quinazolinyl, 2-oxo-1,2-dihydrooxazolo[4,5-g]quinazolinyl, 2-oxo-1,2-dihydrothiazolo[4,5-g]quinazolinyl, 3-oxo-2,3-dihydro-1H-pyrazolo[3,4-g]quinazolinyl, pyrido[2,3-g]quinazolinyl, pyrimidino[4,5-g]cinnolinyl, pyrimidino[4,5-g]quinazolinyl, pyrazino[2,3-g]quinazolinyl, 7-oxo-6,7-dihydropyrido[2,3-g]quinazolinyl, pyrazino[2,3-g]quinazolinyl and 8-oxo-8,9-dihydropyrazino[2,3-g]quinazolinyl. More specifically the tricyclic ring of formula Id is 3H-imidazo[4,5-g]quinazolin-8-yl, oxazolo[4,5-g]quinazolin-8-yl, thiazolo[4,5-g]quinazolin-8-yl, 3H-[1,2,3]triazolo[4,5-g]quinazolin-8-yl, 1H-pyrazolo[3,4-g]quinazolin-8-yl, 6H-pyrrolo[2,3-g]quinazolin-4-yl, 2-oxo-1,2-dihydro-3H-imidazo[4,5-g]quinazolin-8-yl, 2-oxo-1,2-dihydrooxazolo[4,5-g]quinazolin-8-yl, 2-oxo-1,2-dihydrothiazolo[4,5-g]quinazolin-8-yl, 3-oxo-2,3-dihydro-1H-pyrazolo[3,4-g]quinazolin-8-yl, pyrido[-2,3-g]quinazolin-4-yl, pyrimidino[4,5-g]cinnolin-9-yl, pyrimidino[4,5-g]quinazolin-4-yl, pyrazino[2,3-g]quinazolin-4-yl, 7-oxo-6,7-dihydropyrido[2,3-g]quinazolin-4-yl, pyrazino[2,3-g]quinazolin-4-yl or 8-oxo-8,9-dihydropyrazino[2,3-g]quinazolin-4-yl. Further preferred tricyclic rings of formula Id include 3-methyl-3H-imidazo[4,5-g]quinazolin-8-yl, 3-methyl-3H-1,2,3]triazolo[4,5-g]quinazolin-8-yl, 3-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-g]quinazolin-8-yl, pyrazino[2,3-g]quinazolin-4-yl and 9-methyl-8-oxo-8,9-dihydropyrazino[2,3-g]quinazolin-4-yl.
Suitable values for any of the xe2x80x98Rxe2x80x99 groups (R1 to R16), or for various groups within an R1 substituent, or within a substituent on Q2 include:
for halogeno fluoro, chloro, bromo and iodo;
for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl;
for (2-8C)alkenyl: vinyl, allyl and but-2-enyl;
for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl;
for (1-6C)alkoxy: methoxy, ethoxy, propoxy, iopropoxy and butoxy;
for (2-6C)alkenyloxy: vinyloxy and allyloxy;
for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy;
for (1-6C)alkylthio: methylthio, ethylthio and propylthio;
for (1-6C)alkylsulphinyl: methylsulphinyl and ethylsulphinyl;
for (1-6C)alkylsulphonyl: methylsulphonyl and ethylsulphonyl;
for (1-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino;
for di-[(1-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino;
for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl;
for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl;
for N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl;
for (2-6C)alkanoyl: acetyl and propionyl;
for (2-6C)alkanoyloxy: acetoxy and propionyloxy;
for (2-6C)alkanoylamino: acetamido and propionamido;
for N-(1-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and N-methylpropionamido;
for N-(1-6C)alkylsulphamoyl: N-methylsulphamoyl and N-ethylsulphamoy);
for N,N-di-[(1-6C)alkyl]sulphamoyl: N,N-dimethylsulphamoyl;
for (1-6C)alkanesulphonylamino: methanesulphonylamino and ethanesulphonylamino;
for N-(1-6C)alkyl-(1-6C)alkanesulphonylamino: N-methylmethanesulphonylamino and N-methylethanesulphonylamino;
for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido;
for N-(1-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido;
for (3-6C)alkynoylamino: propionamido;
for N-(1-6C)alkyl-(3-6C)alkynoylamino: N-methylpropionamido;
for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl;
for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl;
for di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl;
for halogeno-(1-6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-chloropropyl;
for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;
for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl;
for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl;
for (2-6C)alkanoylamino-(1-6C)alkyl: acetamidomethyl, propionamidomethyl and 2-acetamidoethyl; and
for (1-6C)alkoxycarbonylamino-(1-6C)alkyl: methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl.
A suitable value for (R1)m or for a substituent on Q2 when it is (1-3C)alkylenedioxy is, for example, methylenedioxy or ethylenedioxy and the oxygen atoms thereof occupy adjacent ring positions.
When, as defined hereinbefore, an R1 group forms a group of the formula Q3xe2x80x94X1xe2x80x94 and, for example, X1 is a OC(R4)2 linking group, it is the carbon atom, not the oxygen atom, of the OC(R4)2 linking group which is attached to the quinazoline-like ring such as the ring of formula Ia and the oxygen atom is attached to the Q3 group. Similarly, when, for example a CH3 group within a R1 substituent bears a group of the formula xe2x80x94X3xe2x80x94Q5 and, for example, X3 is a C(R7)2O linking group, it is the carbon atom, not the oxygen atom, of the C(R7)2O linking group which is attached to the CH3 group and the oxygen atom is linked to the Q5 group. A similar convention applies to the attachment of the groups of the formulae Q4xe2x80x94X2xe2x80x94 and xe2x80x94X7xe2x80x94Q7.
As defined hereinbefore, adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R5) or Cxe2x89xa1C. For example, insertion of a Cxe2x89xa1C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4-morpholinobut-2-ynyloxy group and, for example, inspection of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group.
When, as defined hereinbefore, any CH2xe2x95x90CHxe2x80x94 or HCxe2x89xa1Cxe2x80x94 group within a R1 substituent optionally bears at the terminal CH2xe2x95x90 or HCxe2x89xa1 position a substituent such as a group of the formula Q4xe2x80x94X2xe2x80x94 wherein X2 is, for example, NHCO and Q4 is a heterocyclyl-(1-6C)alkyl group, suitable R1 substituents so formed include, for example, N-[heterocyclyl-(1-6C)alkyl]carbamoylvinyl groups such as N-(2-pyrrolidin-1-ylethyl)carbamoylvinyl or N-[heterocyclyl-(1-6C)alkyl]carbamoylethynyl groups such as N-(2-pyrrolidin-1-ylethyl)carbamoylethynyl.
When, as defined hereinbefore, any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents, there are suitably 1 or 2 halogeno substituents present on each said CH2 group and there are suitably 1, 2 or 3 halogeno substituents present on each said CH3 group.
When, as defined hereinbefore, any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent as defined hereinbefore, suitable R1 substituents so formed include, for example, hydroxy-substituted heterocyclyl- (1-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy, hydroxy-substituted amino-(2-6C)alkoxy groups such as 3-amino-2-hydroxypropoxy, hydroxy-substituted (1-6C)alkylamino-(2-6C)alkoxy groups such as 2-hydroxy-3-methylaminopropoxy, hydroxy-substituted di-[(1-6C)alkyl]amino-(2-6C)alkoxy groups such as 3-dimethylamino-2-hydroxypropoxy, hydroxy-substituted heterocyclyl-(1-6C)alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino, hydroxy-substituted amino-(2-6C)alkylamino groups such as 3-amino-2-hydroxypropylamino, hydroxy-substituted (1-6C)alkylamino-(2-6C)alkylamino groups such as 2-hydroxy-3-methylaminopropylamino, hydroxy-substituted di-[(1-6C)alkyl]amino-(2-6C)alkylamino groups such as 3-dimethylamino-2-hydroxypropylamino, hydroxy-substituted (1-6C)alkoxy groups such as 2-hydroxyethoxy, (1-6C)alkoxy-substituted (1-6C)alkoxy groups such as 2-methoxyethoxy and 3-ethoxypropoxy, (1-6C)alkylsulphonyl-substituted (1-6C)alkoxy groups such as 2-methylsulphonylethoxy and heterocyclyl-substituted (1-6C)alkylamino-(1-6C)alkyl groups such as 2-morpholinoethylaminomethyl, 2-piperazin-1-ylethylaminomethyl and 3-morpholinopropylaminomethyl.
A suitable pharmaceutically-acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
According to a further aspect of the invention there is provided a quinazoline derivative of the Formula I 
wherein Q1 is a quinazoline-like ring such as a group of the formula Ia, Ib, Ic or Id 
wherein:
Y1 together with the carbon atoms to which it is attached forms 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S provided that the group of formula Ic so formed is not a purine ring;
Y2 together with the carbon atoms to which it is attached forms a 5- or 6-membered aromatic or partially unsaturated ring comprising 1 to 3 heteroatoms selected from O, N and S;
m is 0, 1, 2, 3 or 4;
each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl cyano, isocyano, nitro, hydroxy, mercapto, amino, formyl, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
Q3xe2x80x94X1xe2x80x94
xe2x80x83wherein X1 is a direct bond or is selected from O, S, SO, SO2, N(R4), CO, CH(OR4), CON(R4), N(R4)CO, SO2N(R4), N(R4)SO2, OC(R4)2, SC(R4)2 and N(R4)C(R4)2, wherein R4 is hydrogen or (1-6C)alkyl, and Q3 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or (R1)m is (1-3C)alkylenedioxy,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, CHxe2x95x90CH and Cxe2x89xa1C wherein R5 is hydrogen or (1-6C)alkyl,
and wherein any CH2xe2x95x90CHxe2x80x94 or HCxe2x89xa1Cxe2x80x94 group within a R1 substituent optionally bears at the terminal CH2xe2x95x90 or HCxe2x89xa1 position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is a direct bond or is selected from CO and N(R6)CO, wherein R6 is hydrogen or (1-6C)alkyl, and Q4 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
xe2x80x94X3xe2x80x94Q5
xe2x80x83wherein X3 is a direct bond or is selected from O, S, SO, SO2, N(R7), CO, CH(OR7), CON(R7), N(R7)CO, SO2N(R7), N(R7)SO2, C(R7)2O, C(R7)2S and N(R7)C(R7)2, wherein R7 is hydrogen or (1-6C)alkyl and Q5 is aryl, aryl-(1-6C)alkyl, (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
xe2x80x94X4xe2x80x94Q8
xe2x80x83wherein X4 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (1-6C)alkyl, and R8 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:
xe2x80x94X5xe2x80x94Q6
xe2x80x83wherein X5 is a direct bond or is selected from O and N(R10), wherein R10 is hydrogen or (1-6C)alkyl, and Q6 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents;
R2 is hydrogen or (1-6C)alkyl and R3 is hydrogen or (1-6C)alkyl, or R2 and R3 together form a CH2, (CH2)2 or (CH2)3 group;
Z is O, S, N(Cxe2x89xa1N) or N(R11), wherein R11 is hydrogen or (1-6C)alkyl; and
Q2 is aryl, aryl-(1-3C)alkyl, aryl-(3-7C)cycloalkyl, heteroaryl, heteroaryl-(1-3C)alkyl or heteroaryl-(3-7C)cycloalkyl wherein each aryl group is phenyl or naphthyl and each heteroaryl group is a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic heteroaryl ring containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, and Q2 is optionally substituted with 1, 2, 3 or 4 substituents, which may be the same or different, selected from halogeno, trifluoromethyl cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino, N-(1-6C)alkyl-(3-6C)alkynoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
xe2x80x94X6xe2x80x94R12
xe2x80x83wherein X6 is a direct bond or is selected from O and N(R13), wherein R13 is hydrogen or (1-6C)alkyl, and R12 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:
xe2x80x94X7xe2x80x94Q7
xe2x80x83wherein X7 is a direct bond or is selected from O, S, SO, SO2, N(R14), CO, CH(OR14), CON(R14), N(R14)CO, SO2N(R14), N(R14)SO2, C(R14)2O, C(R14)2S and C(R14)2N(R14), wherein each R14 is hydrogen or (1-6C)alkyl, and Q7 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, or Q2 is optionally substituted with a (1-3C)alkylenedioxy group,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on Q2 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino and N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, or from a group of the formula:
xe2x80x94X8xe2x80x94R15
xe2x80x83wherein X8 is a direct bond or is selected from O and N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and R15 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on Q2 optionally bears 1 or 2 oxo or thioxo substituents;
or a pharmaceutically-acceptable salt thereof;
provided that the compounds:
1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea.
1-phenyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(3-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(4-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-fluorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-benzyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea and
1-(3-phenylpropyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea are excluded.
Particular novel compounds of the invention include, for example,
(i) quinazoline derivatives of the Formula II 
xe2x80x83wherein each of m R1, R2, R3, Z and Q2 has any of the meanings defined hereinbefore;
(ii) quinoline derivatives of the Formula III 
xe2x80x83wherein each of m, R1, R2, R3, Z and Q2 has any of the meanings defined hereinbefore;
(iii) pyrimidine derivatives of the Formula IV 
xe2x80x83wherein each of m, R1, Y1, R2, R3, Z and Q2 has any of the meanings defined hereinbefore; and
(iv) quinazoline derivatives of the Formula V 
xe2x80x83wherein each of m, R1, Y2, R2, R3, Z and Q2 has any of the meanings defined hereinbefore.
Subject to the provisos described hereinbefore, further particular novel compounds of the invention include, for example, quinazoline derivatives of the Formula II, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of m, R1, R2, R3, Z and Q2 has any of the meanings defined hereinbefore or in paragraphs (a) to (o) hereinafter:
(a) m is 1, 2 or 3, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino and N-(1-6C)alkyl-(3-6C)alkynoylamino, or from a group of the formula:
Q3xe2x80x94X1xe2x80x94
xe2x80x83wherein X1 is a direct bond or is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (1-6C)alkyl, and Q3 is aryl, aryl-(1-6C)alkyl, cycloalkyl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CHxe2x95x90CH and Cxe2x89xa1C wherein R5 is hydrogen or (1-6C)alkyl,
and wherein any CH2xe2x95x90CHxe2x80x94 or HCxe2x89xa1Cxe2x80x94 group within a R1 substituent optionally bears at the terminal CH2xe2x95x90 or HCxe2x89xa1 position a substituent selected from carbamoyl N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is a direct bond or is CO or N(R6)O, wherein R6 is hydrogen or (1-6C)alkyl, and Q4 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of the formula:
xe2x80x94X3xe2x80x94Q5
xe2x80x83wherein X3 is a direct bond or is selected from O, N(R7), CON(R7), N(R7)CO and C(R7)2O, wherein R7 is hydrogen or (1-6C)alkyl, and Q5 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl and (1-6C)alkoxycarbonylamino-(1-6C)alkyl,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(b) m is 1, 2 or 3, and each R1 group, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, (3-6C)alkenoylamino, N-di-(1-6C)alkyl-(3-6C)alkenoylamino, (3-6C)alkynoylamino and N-(1-6C)alkyl-(3 6C)alkynoylamino, or from a group of the formula:
Q3xe2x80x94X1xe2x80x94
xe2x80x83wherein X1 is a direct bond or is selected from O, N(R4), CON(R4), N(R4)CO and OC(R4)2 wherein R4 is hydrogen or (1-6C)alkyl, and Q3 is aryl, aryl-(1-6C)alkyl, heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R5), CON(R5), N(R5)CO, CHxe2x95x90CH and Cxe2x89xa1C wherein R5 is hydrogen or (1-6C)alkyl,
and wherein any CH2xe2x95x90CHxe2x80x94 or HCxe2x89xa1Cxe2x80x94 group within a R1 substituent optionally bears at the terminal CH2xe2x95x90 or HCxe2x89xa1 position a substituent selected from carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is a direct bond or is CO or N(R6)CO, wherein R6 is hydrogen or (1-6C)alkyl, and Q4 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylsulphonyl, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, or from a group of the formula:
xe2x80x94X3xe2x80x94Q5
xe2x80x83wherein X3 is a direct bond or is selected from O, N(R7), CON(R7), N(R7)CO and C(R7)2O, wherein R7 is hydrogen or (1-6C)alkyl, and Q5 is heteroaryl, heteroaryl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, (1-6C)alkyl and (1-6C)alkoxy,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(c) m is 1, 2 or 3, and each R1 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propionamido, or from a group of the formula:
Q3xe2x80x94X1xe2x80x94
xe2x80x83wherein X1 is a direct bond or is selected from O, NH, CONH, NHCO and OCH2 and Q3 is phenyl, benzyl, cyclopropylmethyl, thienyl, 1-imidazolyl, 1,2,3-triazolyl, pyridyl, 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl, 2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, homopiperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethyl or 3-homopiperazin-1-ylpropyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, CONH, NHCO, CHxe2x95x90CH and Cxe2x89xa1C,
and wherein any CH2xe2x95x90CHxe2x80x94 or HCxe2x89xa1Cxe2x80x94 group within a R1 substituent optionally bears at the terminal CH2xe2x95x90 or HCxe2x89xa1 position a substituent selected from carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-methylaminopropyl or 4-dimethylaminobutyl, or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is a direct bond or is CO, NHCO or N(Me)CO and Q4 is pyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-4-ylbutyl,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino and dimethylamino, or from a group of the formula:
xe2x80x94X3xe2x80x94Q5
xe2x80x83wherein X3 is a direct bond or is selected from O, NH, CONH, NHCO and CH2O and Q5 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, aminomethyl, methylaminomethyl, dimethylaminomethyl, acetamidomethyl, methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl and tert-butoxycarbonylaminomethyl,
and wherein any heterocyclyl group within a substituent on R3 optionally bears 1 or 2 oxo substituents;
(d) m is 1, 2 or 3, and each R1 group, which may be the same or different, is selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, propyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, acetamido, propionamido, acrylamido and propionamido, or from a group of the formula:
Q3xe2x80x94X1xe2x80x94
xe2x80x83wherein X1 is a direct bond or is selected from O, NH, CONH, NHCO and OCH2 and Q3 is phenyl, benzyl, thienyl, 1,2,3-triazolyl, pyridyl, 2-(1,2,3-triazolyl)ethyl, 3-(1,2,3-triazolyl)propyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, 1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl, piperidino, piperidin-3-yl, piperidin-4-yl, homopiperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethyl, 3-(1,1-dioxotetrahydro-4H-1,1-thiazin-4-yl)propyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-homopiperidin-1-ylethyl, 3-homopiperidin-1-ylpropyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl, 2-homopiperazin-1-ylethyl or 3-homopiperazin-1-ylpropyl,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, CONH, NHCO, CHxe2x95x90CH and Cxe2x89xa1C,
and wherein any CH2xe2x95x90CHxe2x80x94 or HCxe2x89xa1Cxe2x80x94 group within a R1 substituent optionally bears at the terminal CH2xe2x95x90 or HCxe2x89xa1 position a substituent selected from carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl, aminomethyl, 2-aminoethyl, methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl or 2-dimethylaminoethyl, or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is a direct bond or is CO, NHCO or N(Me)CO and Q4 is pyridyl, pyridylmethyl, 2-pyridylethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino and dimethylamino, or from a group of the formula:
xe2x80x94X3xe2x80x94Q5
xe2x80x83wherein X3 is a direct bond or is selected from O, NH, CONH, NHCO and CH2O and Q5 is pyridyl, pyridylmethyl, pyrrolidin-1-yl, pyrrolidin-2-yl, morpholino, piperidino, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,
and wherein any aryl, heteroaryl or heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl and methoxy,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(e) m is 1 or 2 and the R1 groups, which may be the same or different, are located at the 6- and/or 7-positions and arm selected from hydroxy, amino, methyl, ethyl, propyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, benzyloxy, cyclopropylmethoxy, 2-imidazol-1-ylethoxy, 3-imidazol-1-ylpropoxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy, 2-pyrrolidin-1-ylethylamino, 3-pyrrolidin-1-ylpropylamino, pyrrolidin-3-ylamino, pyrrolidin-2-ylmethylamino, 2-pyrrolidin-2-ylethylamino, 3-pyrrolidin-2-ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethylamino, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperidin-3-ylmethylamino, 2-piperidin-3-ylethylamino, piperidin-4-ylmethylamino, 2-piperidin-4-ylethylamino, 2-homopiperidin-1-ylethylamino, 3-homopiperidin-1-ylpropylamino, 2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino, 2-homopiperazin-1-ylethylamino or 3-homopiperazin-1-ylpropylamino,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, CHxe2x95x90CH and Cxe2x89xa1C,
and when R1 is a vinyl or ethynyl group, the R1 substituent optionally bears at the terminal CH2xe2x95x90 or HCxe2x89xa1 position a substituent selected from N-(2-dimethylaminoethyl)carbamoyl, N-(3-diethylaminopropyl)carbamoyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is a direct bond or is NHCO or N(Me)CO and Q4 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidinylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino and dimethylamino,
and wherein any phenyl, pyridyl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, carbamoyl, methyl, ethyl, methoxy, aminomethyl, acetamidomethyl and tert-butoxycarbonylaminomethyl,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(f) m is 1 or 2 and the R1 groups, which may be the same or different, are located at the 6- and/or 7-positions and are selected from hydroxy, amino, methyl, ethyl, propyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetamido, propionamido, benzyloxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy or 3-homopiperazin-1-ylpropoxy,
and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, CHxe2x95x90CH and Cxe2x89xa1C,
and when R1 is a vinyl or ethynyl group, the R1 substituent optionally bears at the terminal CH2xe2x95x90 of HCxe2x89xa1 position a substituent selected from N-(2-dimethylaminoethyl)carbamoyl or N-(3-dimethylaminopropyl)carbamoyl, or from a group of the formula:
xe2x80x83Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is NHCO or N(Me)CO and Q4 is imidazolylmethyl, 2-imidazolylethyl, 3-imidazolylpropyl, pyridylmethyl, 2-pyridylethyl, 3-pyridylpropyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-piperazin-1-ylethyl or 3-piperazin-1-ylpropyl,
and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, methoxy, methylsulphonyl, methylamino and dimethylamino,
and wherein any phenyl, pyridyl or heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methyl, ethyl and methoxy,
and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents;
(g) each of R2 and R3 is hydrogen or methyl;
(h) each of R2 and R3 is hydrogen;
(i) Z is O, S or N(R11), wherein R11 is hydrogen or (1-6C)alkyl;
(j) Z is O, S, N(R11), wherein R11 is hydrogen, methyl, ethyl or propyl;
(k) Z is O;
(l) Q2 is phenyl, benzyl, t-methylbenzyl phenethyl, naphthyl, 1-(1-naphthyl)ethyl or 2-phenylcyclopropyl which is optionally substituted with 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl cyano, nitro, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoylamino, or from a group of the formula:
xe2x80x94X6xe2x80x94R12
xe2x80x83wherein X6 is a direct bond or is selected from O and N(R13), wherein R13 is hydrogen or (1-6C)alkyl, and R12 is hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl or di-[(1-6C)alkyl]amino-(1-6C)alkyl, or from a group of the formula:
xe2x80x94X7xe2x80x94Q7
xe2x80x83wherein X7 is a direct bond or is selected from O, N(R14), CO, CON(R14), N(R14)CO and C(R14)2O, wherein each R14 is hydrogen or (1-6C)alkyl, and Q7 is phenyl, benzyl, heteroaryl or heteroaryl-(1-6C)alkyl,
and wherein any phenyl or heteroaryl group within a substituent on Q2 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, (1-6C)alkyl and (1-6C)alkoxy;
(m) Q2 is phenyl, benzyl, xcex1-methylbenzyl or phenethyl which is optionally substituted with 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, cyano, nitro, hydroxy, methyl, ethyl, propyl, tert-butyl, vinyl, ethynyl and methoxy, or from a group of the formula:
xe2x80x94X7xe2x80x94Q7
xe2x80x83wherein X7 is a direct bond or is selected from O and CO, and Q7 is phenyl, benzyl, pyridyl or pyridylmethyl, and wherein any phenyl or pyridyl group within a substituent on Q2 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl hydroxy, amino, methyl and methoxy;
(n) Q2 is phenyl, benzyl or phenethyl which is substituted with 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, cyano, nitro, hydroxy, methyl, ethyl, propyl, tert-butyl, vinyl, ethynyl and methoxy provided that at least one substituent is located at an ortho position (for example the 2-position on a phenyl group); and
(o) Q2 is phenyl, benzyl or phenethyl which is substituted with 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, cyano, nitro, hydroxy, methyl, ethyl, propyl, tert-butyl, vinyl, ethynyl and methoxy provided that two substituents are located at ortho positions (for example the 2- and 6-positions on a phenyl group).
Further particular novel compounds of the invention include, for example, quinoline derivatives of the Formula III, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of m, R1, R2, R3, Z and Q2 has any of the meanings defined hereinbefore or in any of the paragraphs (a) to (o) immediately hereinbefore.
Further particular novel compounds of the invention include, for example, pyrimidine derivatives of the Formula IV, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of m, R1, R2, R3, Z and Q2 has any of the meanings defined hereinbefore or in any of the paragraphs (a) to (o) immediately hereinbefore and Y1 has any of the meanings defined hereinbefore or in paragraphs (a) to (c) hereinafter:
(a) bicyclic rings formed by the fusion of ring Y1 to the adjacent pyrimidine ring include thieno[3,2-d]pyrimidin-4-yl, thieno[2,3-d]pyrimidin-4-yl, thiazolo[5,4-d]pyrimidin-7-yl, pyrido[2,3-d]pyrimidin-4-yl, pyrido[3,4-d]pyrimidin-4-yl, pyrido[4,3-d]pyrimidin-4-yl and pyrido[3,2-d]pyrimidin-4-yl;
(b) bicyclic rings formed by the fusion of ring Y1 to the adjacent pyrimidine ring include thieno[3,2-d]pyrimidin-4-yl, pyrido[3,4-d]pyrimidin-4-yl, pyrido[4,3-d]pyrimidin-4-yl and pyrido[3,2-d]pyrimidin-4-yl; and
(c) the bicyclic ring formed by the fusion of ring Y1 to the adjacent pyrimidine ring is thieno[3,2-d]pyrimidin-4-yl.
Further particular novel compounds of the invention include, for example, quinazoline derivatives of the Formula V, or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of m, R1, R2, R3, Z and Q2 has any of the meanings defined hereinbefore or in any of the paragraphs (a) to (o) immediately hereinbefore and Y2 has any of the meanings defined hereinbefore or in paragraphs (a) and (b) hereinafter:
(a) tricyclic rings formed by the fusion of ring Y2 to the adjacent quinazoline ring include 3H-imidazo[4,5-g]quinazolin-8-yl and 2-oxo-1,2-dihydro-3H-imidazo[4,5-g]quinazolin-8-yl; and
(b) tricyclic rings formed by the fusion of ring Y2 to the adjacent quinazoline ring include 3-methyl-3H-imidazo[4,5-g]quinazolin-8-yl and 3-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-g]quinazolin-8-yl.
A preferred compound of the invention is a quinazoline derivative of the Formula II wherein:
m is 1 and the R1 group is located at the 6- or 7-position and is selected from methoxy, benzyloxy, cyclopropylmethoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, N-methylpyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 2-(N-methylpyrrolidin-2-yl)ethoxy, 3-pyrrolidin-2-ylpropoxy, 3-(N-methylpyrrolidin-2-yl)propoxy, 2-(2-oxoimidazolidin-1-yl)ethoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(N-methylpiperidin-3-yl)ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 3-(4-aminomethylpiperidin-1-yl)propoxy, 3-(4-tert-butoxycarbonylaminopiperidin-1-yl)propoxy, 3-(4-carbamoylpiperidin-1-yl)propoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-morpholinobut-2-en-1-yloxy, 4-morpholinobut-2-yn-1-yloxy, 2-(2-morpholinoethoxy)ethoxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-[N-(2-methoxyethyl)-N-methylamino]ethoxy, 3-[N-(2-methoxyethyl)-N-methylamino]propoxy, 2-(2-methoxyethoxy)ethoxy, 3-methylamino-1-propynyl, 3-dimethylamino-1-propynyl, 3-diethylamino-1-propynyl, 6-methylamino-1-hexynyl, 6-dimethylamino-1-hexynyl, 3-(pyrrolidin-1-yl)-1-propynyl, 3-(piperidino)-1-propynyl, 3-(morpholino)-1-propynyl, 3-(4-methylpiperazin-1-yl)-1-propynyl, 6-(pyrrolidin-1-yl)-1-hexynyl, 6-(piperidino)-1-hexynyl, 6-(morpholino)-1-hexynyl, 6-(4-methylpiperazin-1-yl, 1-hexynyl, piperazin-1-yl, 4-methylpiperazin-1-yl, 3-imidazol-1-ylpropylamino, 3-pyrrolidin-1-ylpropylamino, 3-morpholinopropylamino, 3-piperidinopropylamino and 3-piperazin-1-ylpropylamino,
or m is 2 and the R1 groups are located at the 6 and 7-positions, one R1 group is located at the 6 or 7-position and is selected from the groups defined immediately hereinbefore and the other R1 group is a methoxy group;
R2 is hydrogen or methyl;
R3 is hydrogen;
Z is O, S, NH or N(Et); and
Q2 is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl, nitro, methyl, ethyl and methoxy provided that al least one substituent is located at an ortho position;
or a pharmaceutically-acceptable acid-addition salt thereof;
and provided that 1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea is excluded.
A further preferred compound of the invention is a quinazoline derivative of the Formula II wherein:
m is 1 or 2 and the R1 groups, which may be the same or different, are located at the 6- and/or 7-positions and are selected from methoxy, benzyloxy, 2-(1,2,3-triazol-1-yl)ethoxy, 3-(1,2,3-triazol-1-yl)propoxy, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, 2-pyrid-2-ylethoxy, 2-pyrid-3-ylethoxy, 2-pyrid-4-ylethoxy, 3-pyrid-2-ylpropoxy, 3-pyrid-3-ylpropoxy, 3-pyrid-4-ylpropoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, 1-methylpyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 1-methylpyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 2-(1-methylpyrrolidin-2-yl)ethoxy, 3-pyrrolidin-2-ylpropoxy, 3-(1-methylpyrrolidin-2-yl)propoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-pipridinoethoxy, 3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy, 1-methylpiperidin-4-yloxy, piperidin-3-ylmethoxy, 1-methylpiperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, 2-(1-methylpiperidin-3-yl)ethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-(N-methylpiperidin-4-yl)ethoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-morpholinobut-2-en-1-yloxy, 4-morpholinobut-2-yn-1-yloxy, 2-methylsulphonylethoxy, 3-methylsulphonylpropoxy, 2-[N-(2-methoxyethyl)-N-methylamino]ethoxy and 3-[N-(2-methoxyethyl)-N-methylamino]propoxy;
R2 is hydrogen or methyl;
R3 is hydrogen;
Z is O; and
Q2 is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof;
provided that 1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea is excluded.
A further preferred compound of the invention is a quinazoline derivative of the Formula II wherein:
m is 1 and the R1 group is located at the 7-position and is selected from 3-(1,2,3-triazol-1-yl)propoxy, 2-pyrid-4-ylethoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-ylethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-ylmethoxy, N-methylpiperidin-3-ylmethoxy, piperidin-4-ylmethoxy, N-methylpiperidin-4-ylmethoxy, 2-(4-methylpiperazin-1-yl,ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-pyrrolidin-1-ylbut-2-en-1-yloxy, 4-morpholinobut-2-en-1-yloxy, 4-morpholinobut-2-yn-1-yloxy, 3-methylsulphonylpropoxy and 2-[N-(2-methoxyethyl)-N-methylamino]ethoxy;
or m is 2 and one R1 group is located at the 7-position and is selected from the groups defined immediately hereinbefore and the other R1 group is a 6-methoxy group;
R2 is hydrogen or methyl;
R3 is hydrogen;
Z is O, S, NH or N(Et); and
Q2 is phenyl which bears 1, 2 or 3 substituents, which may be the sane or different, selected from fluoro, chloro, bromo, trifluoromethyl, nitro, methyl, ethyl and methoxy provided that at least one substituent is located at an ortho position;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a quinazoline derivative of the Formula II wherein:
m is 1 and the R1 group is located at the 7-position and is selected from 3-(1,2,3-triazol-1-yl)propoxy, 2-pyrid-4-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-morpholinopropoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, N-methylpiperidin-4-ylmethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 4-morpholinobut-2-en-1-yloxy, 4-morpholinobut-2-yn-1-yloxy, 3-methylsulphonylpropoxy and 2-[N-2-methoxyethyl)-N-methylamino]ethoxy;
or m is 2 and one R1 group is located at the 7-position and is selected from the groups defined immediately hereinbefore and the other R1 group is a 6-methoxy group;
R2 is hydrogen or methyl;
R3 is hydrogen;
Z is O; and
Q2 is phenyl which bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo and trifluoromethyl provided that at least one substituent is located at an ortho position;
or a pharmaceutically-acceptable acid-addition salt thereof.
A particular preferred compound of the invention is, for example, a quinazoline derivative of the Formula II selected from:
1-(2,6-dichlorophenyl)-3-[7-(3-morpholinopropoxy)quinazolin-4-yl]urea and
1-(2,6-dichlorophenyl)-3-{7-[3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy]quinazolin-4-yl}urea;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular preferred compound of the invention is, for example, a quinazoline derivative of the Formula II selected from:
1-benzyl-3-[6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]urea and
1-phenethyl-3-[6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]urea;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular preferred compound of the invention is, for example, a quinazoline derivative of the Formula II selected from:
1-(2,6-dichlorophenyl)-3-[6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]urea and
1-(2,6-difluorophenyl)-3-[6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]urea;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further particular preferred compound of the invention is, for example, a quinazoline derivative of the Formula II selected from:
1-(2,6-dimethylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]urea,
1-(2-chloro-6-methylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]urea;
1-(2,6-difluorophenyl)-3-[6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl]urea;
1-(2,6-difluorophenyl)-3-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl]urea;
1-(2,6-dimethylphenyl)-3-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazolin-4-yl]urea;
1-(2,6-dimethylphenyl)-3-[6-methoxy-7-(3-piperidinopropoxy)quinazolin-4-yl]urea;
1-(2,6-dimethylphenyl)-3-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]thiourea and
1-(2-chloro-6-methylphenyl)-3-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]guanidine;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a pyrimidine derivative of the Formula IV wherein the fusion of ring Y1 to the adjacent pyrimidine ring forms a thieno[3,2-d]pyrimidin-4-yl group;
m is 0, or m is 1 and the R1 group is a methyl, ethyl, vinyl or ethynyl group which is located at the 6-position and bears a substituent selected from carboxy, carbamoyl, N-(2-methylaminoethyl)carbamoyl, N-(2-dimethylaminoethyl)carbamoyl, N-(3-methylaminopropyl)carbamoyl or N-(3-dimethylaminopropyl)carbamoyl, or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is NHCO or N(Me)CO and Q4 is 2-imidazol-1-ylethyl, 3-imidazol-1-ylpropyl, 2-pyridylmethyl, 4-pyridylmethyl, 2-pyrid-2-ylethyl, 2-pyrrolidin-1-ylethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, 3-pyrrolidin-1-ylpropyl, 3-(2-oxopyrrolidin-1-yl)propyl, pyrrolidin-2-ylmethyl, 1-methylpyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 2-(1-methylpyrrolidin-2-yl)ethyl, 3-pyrrolidin-2-ylpropyl, 3-(1-methylpyrrolidin-2-yl)propyl, 2-morpholinoethyl, 3-morpholinopropyl, 2-piperidinoethyl, 3-piperidinopropyl, piperidin-3-ylmethyl, 1-methylpiperidin-3-ylmethyl, 2-piperidin-3-ylethyl, 2-(1-methylpiperidin-3-yl)ethyl, piperidinylmethyl, 1-methylpiperidin-4-ylmethyl, 2-piperidin-4-ylethyl, 2-(1-methylpiperidin-4-yl)ethyl, 2-piperazin-1-ylethyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-piperazin-1-ylpropyl or 3-(4-methylpiperazin-1-yl)propyl,
R2 is hydrogen or methyl;
R3 is hydrogen;
Z is O; and
Q2 is phenyl, benzyl or phenethyl which optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo, trifluoromethyl and methyl;
or a pharmaceutically-acceptable acid-addition salt thereof.
A further preferred compound of the invention is a pyrimidine derivative of the Formula IV wherein the fusion of ring Y1 to the adjacent pyrimidine ring forms a thieno[3,2-d]pyrimidin-4-yl group;
m is 0, or m is 1 and the R1 group is a vinyl group located at the 6-position which bears at the terminal CH2xe2x95x90 position a substituent selected from N-(2-dimethylaminoethyl)carbamoyl or N-(3-dimethylaminopropyl)carbamoyl, or from a group of the formula:
Q4xe2x80x94X2xe2x80x94
xe2x80x83wherein X2 is NHCO or N(Me)CO and Q4 is 2-pyridylmethyl, 4-pyridylmethyl, 2-pyrid-2-ylethyl, 2-pyrrolidin-1-ylethyl, 3-(2-oxopyrrolidin-1-yl)propyl, 3-morpholinopropyl, 2-piperidinoethyl or 3-(4-methylpiperazin-1-yl)propyl,
R2 is hydrogen or methyl;
R3 is hydrogen;
Z is O; and
Q2 is phenyl which bears 1, 2 or 3 substituents, which may be the same or different, selected from fluoro, chloro, bromo and trifluoromethyl provided that at least one substituent is located at the ortho position;
or a pharmaceutically-acceptable acid-addition salt thereof.
A particular preferred compound of this aspect of the invention is, for example, a pyrimidine derivative of the Formula II selected from:
1-(2,6-dichlorophenyl)-3-(thieno[3,2-d]pyrimidin-4-yl)urea and
(E)-3-{4-[3-(2,6-dichlorophenyl)ureido]thieno[3,2-d]pyrimidin-6-yl}-N-(3-dimethylaminopropyl)acrylamide;
or a pharmaceutically-acceptable acid-addition salt thereof.
A quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a quinazoline derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, Q1, R2, Z, R3 and Q2 have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
(a) For those compounds of the Formula I wherein R3 is hydrogen and Z is oxygen the reaction, conveniently in the presence of a suitable base, of an amine of the Formula VI
xe2x80x83Q1xe2x80x94NHR2xe2x80x83xe2x80x83VI
xe2x80x83wherein Q1 and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an isocyanate of the Formula VII, or a conventional chemical equivalent thereof or a conventional chemical precusor thereof,
Oxe2x95x90Cxe2x95x90Nxe2x80x94Q2xe2x80x83xe2x80x83VII
xe2x80x83wherein Q2 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate, alkoxide or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium ethoxide, potassium tert-butoxide, sodium hydroxide or potassium hydroxide, or, for example, an alkali metal hydride, for example sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl-lithium or a dialkylamino-lithium, for example lithium di-isopropylamide.
The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, or a dipolar aprotic solvent such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide. The reaction is conveniently carried out at a temperature in the range, for example, 10 to 150xc2x0 C., preferably in the range 20 to 75xc2x0 C.
A suitable conventional chemical equivalent of an isocyanate of the Formula VII is, for example, a compound of the Formula VIII
Lxe2x80x94COxe2x80x94NHxe2x80x94Q2xe2x80x83xe2x80x83VIII
wherein Q2 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, and L is a suitable displaceable or leaving group. On treatment with a suitable base as defined hereinbefore, the compound of the Formula VIII reacts to form the desired isocyanate of the Formula VII.
A suitable displaceable or leaving group L is, for example, a halogeno, alkoxy, aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group.
A suitable conventional chemical precursor of an isocyanate of the Formula VII is, for example, an acyl azide of the Formula IX
N3xe2x80x94COxe2x80x94Q2xe2x80x83xe2x80x83IX
wherein Q2 has any of the meanings defined hereinbefore except that any functional group is protected if necessary. On thermal or photolytic treatment the acyl azide of the Formula IX decomposes and rearranges to form the desired isocyanate of the Formula VII.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which xe2x80x9clowerxe2x80x9d, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention.
A carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example triethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (for example trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed cleavage.
Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups.
Examples of amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl.
The reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley and Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2nd Edition, by T. Green et al., also published by John Wiley and Son, for general guidance on protecting groups.
When L is, for example, a chloro group, the compound of the Formula VIII may be prepared by, for example, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of phosgene with an amine of the Formula X.
H2Nxe2x80x94Q2xe2x80x83xe2x80x83X
The compound of the Formula IX may be prepared by, for example, the reaction of a metal azide such as sodium azide with a compound of the Formula XI.
Lxe2x80x94COxe2x80x94Q2xe2x80x83xe2x80x83XI
(b) For those compounds of the Formula I wherein R3 is hydrogen and Z is sulphur, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of an amine of the Formula VI
xe2x80x83Q1xe2x80x94NHR2xe2x80x83xe2x80x83VI
xe2x80x83wherein Q1 and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an isothiocyanate of the Formula XII, or a conventional chemical equivalent thereof or a conventional chemical precusor thereof,
Sxe2x95x90Cxe2x95x90Nxe2x80x94Q2xe2x80x83xe2x80x83XII
xe2x80x83wherein Q2 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
A suitable conventional chemical equivalent of an isothiocyanate of the Formula XII is, for example, a compound of the Formula XIII
Lxe2x80x94CSxe2x80x94NHxe2x80x94Q2xe2x80x83xe2x80x83XIII
wherein Q2 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, and L is a suitable displaceable group as defined hereinbefore. On treatment with a suitable base as defined hereinbefore, the compound of the Formula XIII reacts to form the desired isothiocyanate of the Formula XII.
A suitable conventional chemical precursor of an isothiocyanate of the Formula XII is, for example, an acyl azide of the Formula XIV
N3xe2x80x94CSxe2x80x94Q2xe2x80x83xe2x80x83XIV
wherein Q2 has any of the meanings defined hereinbefore except that any functional group is protected if necessary. On thermal or photolytic treatment the thioacyl azide of the Formula XIV decomposes and rearranges to form the desired isothiocyanate of the Formula XII.
When L is, for example, a chloro group, the compound of the Formula XIII may be prepared by, for example, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of thiophosgene with an amine of the Formula X.
H2Nxe2x80x94Q2xe2x80x83xe2x80x83X
The compound of the Formula XIV may be prepared by, for example, the reaction of a metal azide such as sodium azide with a compound of the Formula XV.
Lxe2x80x94COxe2x80x94Q2xe2x80x83xe2x80x83XV
(c) For those compounds of the Formula I wherein R2 is hydrogen and Z is oxygen, the reaction, conveniently in the presence of a suitable base, of an amine of the Formula XVI
R3NHxe2x80x94Q2xe2x80x83xe2x80x83XVI
xe2x80x83wherein Q2 and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an isocyanate of the Formula XVII, or a conventional chemical equivalent thereof or a conventional chemical precusor thereof,
Q1xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83XVII
xe2x80x83wherein Q1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
A suitable conventional chemical equivalent of an isocyanate of the Formula XVII is, for example, a compound of the Formula XVIII
Q1xe2x80x94NHxe2x80x94COxe2x80x94Lxe2x80x83xe2x80x83XVIII
wherein Q1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, and L is a suitable displaceable group as defined hereinbefore. On treatment with a suitable base as defined hereinbefore, the compound of the Formula XVIII reacts to form the desired isocyanate of the Formula XVII.
A suitable conventional chemical precursor of an isocyanate of the Formula XVII is, for example, an acyl azide of the Formula XIX
Q1xe2x80x94COxe2x80x94N3xe2x80x83xe2x80x83XIX
wherein Q1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary. On thermal or photolytic treatment the thioacyl azide of the Formula XIX decomposes and rearranges to form the desired isocyanate of the Formula XVII.
When L is, for example, a chloro group, the compound of the Formula XVIII may be prepared by, for example, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of phosgene with an amine of the Formula XX.
Q1xe2x80x94NH2xe2x80x83xe2x80x83XX
The compound of the Formula XIX may be prepared by, for example, the reaction of a metal azide such as sodium azide with a compound of the Formula XXI.
Q1xe2x80x94COxe2x80x94Lxe2x80x83xe2x80x83XXI
(d) For those compounds of the Formula I wherein R2 is hydrogen and Z is sulphur, the reaction, conveniently in the presence of a suitable base, of an amine of the Formula XVI
R3NHxe2x80x94Q2xe2x80x83xe2x80x83XVI
xe2x80x83wherein Q2 and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an isothiocyanate of the Formula XXII, or a conventional chemical equivalent thereof or a conventional chemical precusor thereof,
Q1xe2x80x94Nxe2x95x90Cxe2x95x90Sxe2x80x83xe2x80x83XXII
xe2x80x83wherein Q1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, whereafter any protecting group that is present is removed by conventional means.
A suitable conventional chemical equivalent of an isothiocyanate of the Formula XXII is, for example, a compound of the Formula XXIII
Q1xe2x80x94NHxe2x80x94CSxe2x80x94Lxe2x80x83xe2x80x83XXIII
wherein Q1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary, and L is a suitable displaceable group as defined hereinbefore. On treatment with a suitable base as defined hereinbefore, the compound of the Formula XXIII reacts to form to desired isothiocyanate of the Formula XXII.
A suitable conventional chemical precursor of an isothiocyanate of the Formula XXII is, for example, an acyl azide of the Formula XXIV
Q1xe2x80x94CSxe2x80x94N3xe2x80x83xe2x80x83XXIV
wherein Q1 has any of the meanings defined hereinbefore except that any functional group is protected if necessary. On thermal or photolytic treatment the thioacyl azide of the Formula XXIV decomposes and rearranges to form the desired isothiocyanate of the Formula XXII.
When L is, for example, a chloro group, the compound of the Formula XXIII may be prepared by, for example, the reaction, conveniently in the presence of a suitable base as defined hereinbefore, of thiophosgene with an amine of the Formula XX.
Q1xe2x80x94NH2xe2x80x83xe2x80x83XX
The compound of the Formula XXIV may be prepared by, for example, the reaction of a metal azide such as sodium azide with a compound of the Formula XXV.
Q1xe2x80x94CSxe2x80x94Lxe2x80x83xe2x80x83XXV
(e) For those compounds of the Formula I wherein a substituent on Q1 or Q2 contains an alkylcarbamoyl group or a substituted alkylcarbamoyl group, the reaction of the corresponding compound of Formula I wherein a substituent on Q1 or Q2 is a carboxy group, or a reactive derivative thereof, with an amine or substituted amine as appropriate.
A suitable reactive derivative of a compound of Formula I wherein a substituent on Q1 or Q2 is a carboxy group is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, an ester formed by the reaction of the acid and an ester such as pentafluorophenyl trifluoroacetate or an ester formed by the reaction of the acid and an alcohol such as N-hydroxybenzotriazole; an acyl azide, for example an azide formed by the reaction of the acid and an azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide; or the product of the reaction of the acid and a carbodiimide such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
The reaction is conveniently carried out in the presence of a suitable base as defined hereinbefore and in the presence of a suitable inert solvent or diluent as defined hereinbefore.
Typically a carbodiimide coupling reagent is used in the presence of an organic solvent (preferably an anhydrous polar aprotic organic solvent) at a non-extreme temperature, for example in the region xe2x88x9210 to 40xc2x0 C., typically at ambient temperature of about 20xc2x0 C.
A compound of Formula I wherein a substituent on Q1 or Q2 is a carboxy group may conveniently be prepared by the cleavage of the corresponding ester such as a (1-12C)alkyl ester, for example by acid-, base- metal- or enzymatically-catalysed cleavage.
(f) For those compounds of the Formula I wherein a substituent on Q1 or Q2 contains an amino-(1-6C)alkyl group, the cleavage of the corresponding compound of Formula I wherein a substituent on Q1or Q2 is a protected amino-(1-6C)alkyl group.
Suitable protecting groups for an amino-(1-6C)alkyl group are, for example, any of the protecting groups disclosed hereinbefore for an amino group. Suitable methods for the cleavage of such amino protecting groups are also disclosed hereinbefore. In particular, a suitable protecting group is a lower alkoxycarbonyl group such as a tert-butoxycarbonyl group which may be cleaved under conventional reaction conditions such as under acid-catalysed hydrolysis.
(g) For those compounds of the Formula I wherein Z is a N(R11) group wherein R11 is hydrogen or (1-6C)alkyl, the reaction, conveniently in the presence of a suitable metallic salt catalyst, of a thiourea of the Formula I wherein Q1, Q2, R2 and R3 have any of the meanings defined hereinbefore except that any functional group is protected if necessary and Z is sulphur, with an amine of formula R11NH2, whereafter any protecting group that is present is removed by conventional means.
A suitable metallic salt catalyst is, for example, a mercuric salt such as mercuric(II) oxide and the reaction is conveniently carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore.
(h) For those compounds of the Formula I wherein a substituent on Q1 or Q2 contains an amino group, the reduction of a corresponding compound of Formula I wherein a substituent on Q1 or Q2 contains a nitro group.
Typical reaction conditions include the use of ammonium formate or hydrogen gas in the presence of a catalyst, for example a metallic catalyst such as palladium-on-carbon. Alternatively a dissolving metal reduction may be carried out, for example using iron in the presence of an acid, for example an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric or acetic acid. The reaction is conveniently carried out in the presence of an organic solvent (preferably a polar protic solvent) and preferably with heating, for example to about 60xc2x0 C. Any functional groups are protected and deprotected as necessary.
When a pharmaceutically-acceptable salt of a quinazoline derivative of the Formula I is required, for example an acid-addition salt, it may be obtained by, for example, reaction of said quinazoline derivative with a suitable acid using a conventional procedure.
The following assays can be used to measure the effects of the compounds of the present invention as p56lck inhibitors, as inhibitors of T cell activation, as inhibitors of cytokine production in mice and as inhibitors of transplant rejection.
(a) In Vitro Enzyme Assay
The ability of test compounds to inhibit phosphorylation by the enzyme p56lck of a tyrosine-containing polypeptide substrate was assessed using a conventional Elisa assay.
The following conventional procedure was used to obtain p56lck enzyme. An EcoRI/NotI fragment containing the entire coding sequence of p56lck was generated by the technique of polymers chain reaction (PCR) from Incyte clone No. 2829606. A 6-His tag was added to the sequence at the N-terminus during the PCR stage. Conventional sequence, analysis identified a number of changes compared to the published sequence and this were found also to have been present in the original Incyte template. To achieve expression of the enzyme, the PCR fragment was inserted downstream of the polyhedrin promotor of pFASTBAC1 (Life Techinologies Limited, Paisley, UK, Catalogue No. 10360-014). A recombinant Baculovirus was constructed using the Bac-to-Bac system (Life Technologies Limited). High Five insect cells (Invitrogen BV, PO Box 2312, 9704 CH Groningen, The Netherlands, Catalogue No. B855-02) were infected with the recombinant Baculovirus at a multiplicity of infection of 1 and incubated for 48 hours. The cells were harvested. Groups of 1.6xc3x97109 cells were lysed by incubation in 20 mM Hepes pH7.5 buffer containing 10% glycerol, 1% Triton-X-100, magnesium chloride (1.5 mM), ethylene glycol bisthaminoethyl ether N,N,Nxe2x80x2,Nxe2x80x2-tetraactic acid) (EGTA, 1 mM), sodium vanadate (1 mM), sodium fluoride (10 mM), imidazole (5 mM), sodium chloride (150 mM), phenylmethanesulphonyl fluoride (0.1 mM), pepstatin (1 mg/ml) and leupeptin (1 mg/ml). A soluble fraction was obtained by centrifugation and His-p56lck was purified by column chromatography on a 1 ml Ni-NTA agarose column (Qiagen Limited, Crawley, West Sussex, UK). The protein was eluted using the above-mentioned buffer except that imidazole (100 mM) was also present. The p56lck enzyme so obtained was stored at xe2x88x9280xc2x0 C.
Substrate solution [100 xcexcl of a 24 xcexcg/ml solution of the polyamino acid Poly(Glu, Ala, Tyr) 6:3:1 (Sigma Catalogue No. P3899) in phosphate buffered salin (PBS)] was added to each well of a Nunc 96-well immunoplate (Catalogue No. 439454) and the plate was sealed and stored at 4xc2x0 C. for 16 hours. The process of substrate solution was discarded, the substrate-coated wells were washed with Hepes pH7.4 buffer (50 mM, 300 xcexcl) and blotted dry. Each test compound was dissolved in DMSO and diluted to give a series of dilutions (from 100 xcexcM to 0.0001 xcexcM) of the compound in a 10:1 mixture of water and DMSO. Portions (25 xcexcl) of each dilution of test compound were transferred to the 96-well assay plate. Aliquots (25 xcexcl) of a 10:1 mixture of water and DMSO were added followed by aliquots (25 xcexcl) of a mixture of adenosine triphosphate (ATP; 24 xcexcl of a 1 mM aqueous solution) and manganese chloride (3 ml of a 40 mM aqueous solution).
p56lck enzyme (0.3 xcexcl of a 0.5 mg/ml stock solution) was diluted in a mixture of Hepes pH 7.4 buffer (200 mM, 3 ml), sodium orthovanadate (2 mM, 0.6 ml), 1% Triton X-100 (0.6 ml), dithiothreitol (25 mM, 48 xcexcl) and distilled water (1.8 ml). Aliquots (50 xcexcl) of the resultant solution were transferred to each well in the assay plate and the plate was incubated at ambient temperature for 8 minutes. The wells were washed sequentially with two aliquots (300 xcexcl) of phosphate-buffered saline (PBS) containing 0.1% Tween 20 (hereinafter PBS/T).
Aliquots (100 xcexcl) were added to each well of a mixture of antiphosphotyrosine-4G10 monoclonal IgG2bk antibody (UBI Catalogue No. 05-321; 30 xcexcl of a 50 xcexcg/ml solution of the antibody in PBS/T), PBS/T (11 ml) and bovine serum albumin (BSA; Sigma Catalogue No. A6793; 55 mg) and the plate was incubated at ambient temperature for 1 hour. The wells were washed sequentially with two aliquots (300 xcexcl) of PBS/T and blotted dry. Aliquots (100 xcexcl) were added to each well of a mixture of sheep anti-mouse IgG-peroxidase antibody (Amersham Catalogue No. NXA931; 20xcexcl), PBS/T (11 ml) and BSA (55 mg) and the plate was incubated at ambient temperature for 1 hour. The wells were washed sequentially with two aliquots (300 xcexcl) of PBS/T and blotted dry.
Aliquots (100 xcexcl) were added to each well of an ABTS solution [prepared by adding an 2,2xe2x80x2-azinobis(3-ethylbenzothiazolinesulphonic acid) (ABTS) tablet (50 mg; Boehringer Catalogue No. 1204521) to a mixture (50 mM) of phosphate-citrate pH5.0 buffer and 0.03% sodium perforate (obtained by adding a PCSB capsule (Sigma Catalogue No. P-4922) to distilled water (100 ml)]. The plate was incubated at ambient temperature for 1.5 hours and the absorbance at 405 nm was determined.
The extent of inhibition of the phosphorylation reaction at a range of concentrations of each test compound was determined and an IC50 value was calculated.
(b) In Vitro T Cell Proliferation Assays
The ability of test compounds to inhibit T cell proliferation was assessed by using human peripheral blood mononuclear cells and stimulation of the T cells by way of the T cell receptor or other than by way of the T cell receptor.
Peripheral blood mononuclear cells (PBMC) were isolated from heparinised (10 units/ml heparin) human blood by density centrifugation (Lymphoprep(trademark); Nycomed) spinning initially at 2000 rpm at ambient temperature for 20 minutes. Cells at the interphase were transferred to clean tubes, diluted 1:1 with RPMI 1640 medium (Gibco) and spun at 2000 rpm at ambient temperature for 10 minutes. The cell pellet was resuspended in RPMI 1640 medium and spun at 1400 rpm at ambient temperature for 10 minutes. The cell pellet was resuspended in RPMI 1640 medium and spun at 90 rpm at ambient temperature for 10 minutes to remove platelets. The prepared mononuclear cells were resuspended in an assay medium comprising RPMI 1640 culture medium supplemented with 50 units/ml penicillin, 50 xcexcg/ml streptomycin, 1 mM glutamine and 10% beat-inactivated human AB serum.
Test compounds were solubilities in DMSO at a concentration of 10 mM and diluted 1:83.3 in assay medium. Aliquots (75 xcexcl) were added to each well of a 96 well flat-bottomed tissue culture plate and subsequently serial 1 to 3 dilutions were made into assay medium giving final test concentrations in the range 0.1 to 30 xcexcM. Control wells contained assay medium (50 xcexcl) containing 1.2% DMSO. PBMCs (100 xcexcl of a suspension of 2xc3x97106 cell/ml in assay medium) were added to each well and incubated for 1 hour at 37xc2x0 C. in a humidified (5% CO2/95% air) incubator.
The extent of inhibition of T cell proliferation at a range of concentrations of each test compound was determined and an IC50 value was calculated.
(b)(i) T Cell Receptor Stimulation
Aliquots (50 xcexcl) of the T cell receptor stimulatory anti-CD3 antibody (Pharmingen Catalogue No. 30100D; 40 ng/ml in assay medium) were added to each well and the cells were incubated for 24 hours at 37xc2x0 C. in a humidified (5% CO2/95% air) incubator. Triturated thymidine (1 xcexcCi per well) was added and the cells were incubated for up to a further 24 hours at 37xc2x0 C. The cells were harvested onto a filter mat and radioactivity was counted using a Wallac 1450 Microbeta Plus liquid scintillation counter.
(b)(ii) Non T Cell Receptor Stimulation
Aliquots (50 xcexcl) of a mixture of the cell stimulants PMA (phorbol-12-myrstate-13-acetate, Sigma Catalogue No. P8139; 40 ng/ml) and Ionomycin (Sigma Catalogue No. 10684; 1.2 xcexcM) were added to each well and the cells were incubated and analysed as described in paragraph (b)(i).
(c) In Vivo Skin Graft Rejection Test
The ability of test compounds to inhibit rodent skin allograft rejection was assessed using analogous procedures to those disclosed by J. Magae et al., Cellular Immunology, 1996, 173, 276-281 and R. Tsuji et al., J. Antibiot., 1992, 45, 1295 to assess the effect of cyclosporin A on T cell properties in vivo.
(d) Test as Anti-arthritic Agent
Activity of a test compound as an anti-arthritic agent was assessed as follows. Acid soluble native type II collagen has been shown to be arthritogenic in rats causing polyarthritis when administered in Freunds incomplete adjuvant by (D. E. Trentham et al. J. Exp. Med., 1977, 146, 857). This is now known as collagen-induced arthritis (CIA) and similar conditions can be induced in mice and primates. CIA in DBA/1 mice as described by R. O. Williams et al., Proc Natl. Acad Sci. 1992, 89, 9784 and Immunology, 1995, 84, 433 is a tertiary model which can be used to demonstrate the anti-arthritic activity of a test compound.
Although the pharmacological properties of the compounds of the Formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I, including those compounds excluded by way of one of the provisos in the definition hereinbefore, may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d):
Test (a): IC50 in the range, for example, 0.0001-5 xcexcM;
Test (b)(i): IC50 in the range, for example, 0.001-10 xcexcM;
Test (b)(ii): IC50 in the range, for example, 0.5xe2x86x9230 xcexcM;
Test (c): activity in the range, for example, 0.1-100 mg/kg;
Test (d): activity in the range, for example, 1-100 mg/kg;
No physiologically-unacceptable toxicity was observed at the effective dose for compounds tested of the present invention. Accordingly no untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore but without the proviso that the group of formula Ic so formed is not a purine ring and including the compounds:
1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea,
1-phenyl-3-pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidinyl)urea,
1-(3-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(4-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-fluorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-benzyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea and
1-(3-phenylpropyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
is administered at the dosage ranges defined hereinafter.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insulation (for example as a finely divided powder) or for parent administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarly vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration is however preferred, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
According to a further aspect of the invention there is provided a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
We have found that the compounds of the present invention are of use in the prevention or treatment of autoimmune diseases or medical conditions, for example T cell mediated disease such as transplant rejection, rheumatoid arthritis or multiple sclerosis. We have further found that these effects are believed to arise by virtue of inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to full T cell activation, for example by way of inhibition of the enzyme p56lck. Accordingly the compounds of the present invention are expected to be useful in the prevention or treatment of T cell mediated diseases or medical conditions. In particular the compounds of the present invention are expected to be useful in the prevention or treatment of those pathological conditions which are sensitive to inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to T cell activation, for example by way of inhibition of p56lck tyrosine kinase. Further, the compounds of the present invention are expected to be useful in the prevention or treatment of those diseases or medical conditions which are mediated alone or in part by inhibition of the enzyme p56lck, i.e. the compounds may be used to produce a p56lck enzyme inhibitory effect in a warm-blooded animal in need of such treatment. Specifically, the compounds of the present invention are expected to be useful in the prevention or treatment of autoimmune conditions or diseases such as inflammatory diseases (for example rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis and lung fibrosis), multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, allergic asthma and insulin-dependent diabetes. In particular the compounds of the present invention are expected to be useful in the prevention or treatment of the acute rejection of transplanted tissue or organs.
Thus according to this aspect of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore but without the proviso that the group of formula Ic so formed is not a purine ring and including the compounds:
1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea,
1-phenyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(3-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(4-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-fluorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-benzyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea and
1-(3-phenylpropyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
in the manufacture of a medicament for use in the prevention or treatment of T cell mediated diseases or medical conditions in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention them is provided a method for the prevention or treatment of T cell mediated diseases or medical conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore but without the proviso that the group of formula Ic so formed is not a purine ring and including the compounds:
1-(6,7-dimethoxyquinazolin-4-yl)-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-phenylurea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea,
1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-methoxyphenyl)urea,
1-phenyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(3-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(4-chlorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-(2-fluorophenyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea,
1-benzyl-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea and
1-(3-phenylpropyl)-3-(pyrazolo[3,4-d]pyrimidin-4-yl)urea.
According to a further feature of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined immediately hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those pathological conditions which are sensitive to inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to T cell activation.
According to a further feature of the invention there is provided a method for the prevention or treatment of those pathological conditions which are sensitive to inhibition of one or more of the multiple tyrosine-specific protein kinases which are involved in the early signal transduction steps which lead to T cell activation which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined immediately hereinbefore.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of T cell mediated disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. A unit dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight, preferably 0.1 mg/g to 30 mg/kg body weight, is envisaged, given if required in divided doses.
The compounds of this invention may be used in combination with other drugs and therapies used in the treatment of T cell mediated disease. For example, the compounds of the Formula I could be used in combination with drugs and therapies used in the treatment of autoimmune conditions or diseases such as inflammatory diseases (for example rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis and lung fibrosis), multiple sclerosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, allergic asthma and insulin-dependent diabetes. In particular the compounds of the Formula I could be used in combination with drugs and therapies such as cyclosporin A used in the prevention or treatment of the acute rejection of transplanted organs.
For example, the compounds of the Formula I are of value in the treatment of certain inflammatory and non-inflammatory diseases which are currently treated with a cyclooxygenase-inhibitory non-steroidal anti-inflammatory drug (NSAID) such as indomethacin, ketorolac, acetylsalicyclic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-adminstration of a compound of the Formula I with a NSAID can result in a reduction of the quantity of the latter agent needed to produce a therapeutic effect. Thereby the likelihood of adverse side-effects from the NSAID such as gastrointestinal effects are reduced. Thus according to a further feature of the invention there is provided a pharmaceutical composition which comprises a compound of the Formula I, or a pharmaceutically-acceptable salt thereof, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent, and a pharmaceutically-acceptable diluent or carrier.
The compounds of the invention may also be used with anti-inflammatory agents such as an inhibitor of the enzyme 5-lipoxygenase. The compounds of the invention may also be used with anti-inflammatory agents such as an inhibitor of the enzyme COX-2 such as celecoxib or rofecoxib.
The compounds of the Formula I may also be used in the treatment of conditions such as rheumatoid arthritis in combination with antiarthritic agents such as gold, methotrexate, steroids and penicillinamine, and in conditions such as osteoarthritis in combination with steroids.
The compounds of the present invention may also be administered in degradative diseases, for example osteoarthritis, with chondroprotective, anti-degradative and/or reparative agents such as Diacerhein, hyaluronic acid formulations such as Hyalan, Rumalon, Arteparon and glucosamine salts such as Antril.
The compounds of the Formula I may be used in the treatment of asthma in combination with antiasthmatic agents such as bronchodilators and leukotnene antagonists.
If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate.
Although the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of T cell activation. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:
(i) operations were carried out at ambient temperature, it, in die range 17 to 25xc2x0 C. and under an atmosphere of an inert gas such as argon unless otherwise stated;
(ii) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;
(iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck. Darmstadt, Germany or high pressure liquid chromatography (HPLC) was performed on C18 reverse phase silica, for example on a Dynamax C-18 60xc3x85 preparative reversed-phase column;
(iv) yields, where present, arm given for illustration only and are not necessarily the maximum attainable;
(v) in general, the end-products of the Formula I have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer and, where appropriate, either positive ion data or negative ion data were collected; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Jeol JNM EX 400 spectrometer operating at a field strength of 400 MHz, a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz or a Bruker AM300 spectrometer operating at a field strength of 300 MHz]; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad;
(vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, HPLC, infra-red (IR) and/or NMR analysis;
(vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; and
(viii) the following abbreviations have been used:
DMF N,N-dimethylformamide
DMSO dimethylsulphoxide
THF tetrahydrofuran